EXERCISE TRAINING PROTECTS MYOCARDIAL MITOCHONDRIA AGAINST ISCHEMIA ...

EXERCISE TRAINING PROTECTS MYOCARDIAL MITOCHONDRIA AGAINST ISCHEMIA REPERFUSION-INDUCED INJURY

By YOUNGIL LEE

A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT

OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2008 1

? 2008 Youngil Lee 2

To the numerous teachers and professors who contributed to my education; and to my wife, children, parents, and friends for their continuous support

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ACKNOWLEDGMENTS This project could not have been completed without the cooperation of many individuals. Above all, I would like to convey my most heartfelt appreciation to my committee chair and mentor, Dr. Scott Powers, for his unending support and encouragement throughout my doctoral program at the University of Florida. His enthusiasm, availability, and dedication to work with me on the problems we encountered with the projects were unwavering. Watching the commitment and enthusiasm that Dr. Powers brings to work each day has had a great impact on my scientific career. I would also like to acknowledge supervisory committee. I thank Dr. Stephen Dodd for his assistance during my doctoral career. I thank Dr. David Criswell for his willingness to discuss science and the project. I thank Dr. James Jessup for providing me with research ideas that link basic science questions to clinical problems. Additionally, I would like to thank two past postdoctoral fellows, Dr. Karyn Hamilton and Dr. John Quindry for their guidance and help during my first years in the laboratory. Many of my coworkers also contributed to the success of this project. These individuals include Kisuk Min, Erin Talbert, Andreas Kavazis, Joseph McClung, Melissa Whidden, and Darin Falk. Most importantly, I would like to express my special gratitude to my wife, Hyunjoo, and my children, Austin and Rachel, who have always been my greatest source of support, encouragement, and strength. A portion of this degree belongs to them.

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TABLE OF CONTENTS

page

ACKNOWLEDGMENTS ...............................................................................................................4

LIST OF TABLES...........................................................................................................................8

LIST OF FIGURES .........................................................................................................................9

ABSTRACT...................................................................................................................................11

CHAPTER

1 INTRODUCTION ..................................................................................................................13

2 REVIEW OF RELATED LITERATURE..............................................................................16

Introduction.............................................................................................................................16 Myocardial Ischemia-Reperfusion Injury...............................................................................16

Levels of Injury ...............................................................................................................16 Events Leading to Myocardial Ischemia-Reperfusion Injury .........................................17 Ischemia Reperfusion-induced Cellular Oxidative Stress: An Overview .......................18

Myocardial protein oxidation ...................................................................................19 Myocardial lipid peroxidation..................................................................................19 Sources of ROS.......................................................................................................................20 Mitochondria and IR Damage ................................................................................................21 Mitochondrial Antioxidants....................................................................................................22 Superoxide Dismutase (SOD) .........................................................................................22 Catalase............................................................................................................................23 Glutathione Peroxidase (GPx) .........................................................................................23 Glutathione (GSH)...........................................................................................................23 Peroxiredoxin 3 (Prx3) ....................................................................................................24 Thioredoxin 2 (Trx2).......................................................................................................24 Thioredoxin Reductase 2 (TrxR2)...................................................................................24 Mitochondrial Antioxidant Network ......................................................................................25 Two Subpopulations of Mitochondria Exist in Cardiomyocytes ...........................................25 Exercise-Induced Cardioprotection against IR Injury ............................................................26 Endoplasmic Reticulum (ER) Proteins............................................................................26 Cyclooxygenase-2 (COX-2) Activity..............................................................................27 Elevated Myocardial Heat Shock Proteins ......................................................................27 Sarcolemmal ATP-dependent Potassium Channel (sarcoKATP)......................................28 Exercise Protects the Heart against IR-induced Calpain Activation ...............................28 Improved Antioxidant Capacity ......................................................................................28 Exercise and Mitochondrial Protection ..................................................................................29 Summary.................................................................................................................................30

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